Amifostine (Ethyol [R], WR-2721) is a cytoprotective drug that has been approved by the U.S. FDA for intravenous administration in cancer patients receiving radiation therapy and certain forms of chemotherapy. The chemoprotective and radioprotective benefits of amifostine remain grossly underutilized not because of limitations of efficacy but mainly because its administration is limited to intravenous and subcutaneous routes. Amifostine is not effective when administered orally - one of the most preferred routes of drug administration. Three years ago we began an effort to overcome this limitation by developing a formulation where amifostine's premature inactivation in the gastrointestinal tract was prevented due to its incorporation in a protective polymeric matrix. The results of this effort and published work by others clearly indicate that the development of such a formulation is indeed quite feasible. In the current application, we therefore propose to follow up on our initial success in developing a prototype of orally active sustained release formulation of amifostine. While our prototype formulation clearly establishes the scientific validity of our approach, its practical application in clinic demands extensive optimization and rigorous testing which we propose in this application as the logical extension of our current work. We hypothesize that amifostine can be successfully formulated to provide an oral dosage form with significant chemo-and radioprotection under clinical settings. The following specific aims delineate the step-wise approach towards such development: (I) Optimize the prototype sustained release nanoeapsule formulation of amifostine: Prepare new batches using the spray-drying technique and optimize processing parameters to: a) obtain desired particle size distribution and particle morphology, b) maximize the yield, c) maximize the efficiency of encapsulation, and d) minimize the presence of residual solvent; (II) Optimize for in vitro amifostine release characteristics to obtain one formulation with 20%-30% initial drug release followed by continued release for 3 days, and another formulation with 5%-10% initial drug release followed by continued release for 7 days; (lII) Conduct in viva studies using CD2F1 male mice to: a) Evaluate relative bioavailability of amifostine b) Optimize the absorption and tissue distribution characteristics and c) Evaluate and optimize for radioproteetive efficacy against both acute whole body gamma irradiation (9.0 GY) and fractionated whole body gamma irradiation (three consecutive treatments of 3.0 GY/day). The radioprotective efficacy will be measured using the following parameters: 30-day survival, changes in intestinal permeability, jejunal crypt cell survival, and bone marrow hemopoietic progenitor cell survival (erythroids and granulocytes/monocytes); and (IV) Evaluate the long-term (up to six months) thermal stability of the two best formulations. Following the successful preclinlcal evaluations in mice, this novel delivery system can be used, in the future, for evaluation in dogs followed by human clinical trials. Development of such a formulation will mark an important advancement in the field of chemoprotection and radioprotection during cancer therapy.